CN106279164B

CN106279164B - 5 type phosphodiesterase inhibitors and its application

Info

Publication number: CN106279164B
Application number: CN201510359738.1A
Authority: CN
Inventors: 陈中祝; 徐志刚; 唐典勇
Original assignee: Chongqing Dicongle Pharmaceutical Co Ltd
Current assignee: Chongqing Dicongle Pharmaceutical Co., Ltd.
Priority date: 2015-06-26
Filing date: 2015-06-26
Publication date: 2019-11-01
Anticipated expiration: 2035-06-26
Also published as: CN106279164A

Abstract

Disclose as 5 type phosphodiesterase inhibitors formula (I) expression compound or its pharmaceutically acceptable salt and its treat and/or prevent mammal disease relevant to 5 type phosphodiesterases or morbid state in purposes,

Description

5 type phosphodiesterase inhibitors and its application

Technical field

This application involves field of medicaments, 5 type phosphodiesterase (PDE5) inhibitor more particularly, to selectivity and its Application in treatment and/or prevention disease or morbid state, wherein this inhibit to be considered beneficial.

Background technique

Erectile dysfunction (ED) has important influence to male psychology and physiology.Research finds PDE5 inhibitor energy Effectively treatment ED.For example, the Xi Aili (Cialis) of Li Lai company, chemical structure is as follows:

Research finds that PDE5 inhibitor can improve the ED as caused by many reasons, and for onset time, Difference between each compound is little, but for half-life period, differing greatly between each compound.For example, Xi Aili exists The intracorporal long half time of people was up to 24~36 hours, and the Chinese mugwort of the viagra of Pfizer company production and Bayer Pharmaceuticals Corp's production The half-life period of power up to both drugs is then only about 4~5 hours.

Since the half-life period of drug is different, the people of all ages and classes and different constitutions can select the product with different half-life period To meet different needs.But there is huge differences between the half-life period of these three above-mentioned drugs.Therefore, it still needs 5 new type phosphodiesterase inhibitors.

Summary of the invention

On the one hand, this application involves the compound indicated by formula (I) or its pharmaceutically acceptable salt,

On the other hand, this application involves pharmaceutical compositions, and it includes the compound indicated by formula (I) or its drug are acceptable Salt and pharmaceutically acceptable carrier, excipient or diluent,

On the other hand, this application involves the compound indicated by formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition Object is in preparation for treating and/or preventing the disease relevant to 5 type phosphodiesterases of mammal or the drug of morbid state In purposes, wherein inhibit 5 type phosphodiesterases be considered as it is beneficial,

On the other hand, this application involves the compound indicated by formula (I) or its pharmaceutically acceptable salt or its pharmaceutical composition Purposes of the object in the drug for preparing the erectile dysfunction for treating and/or preventing people,

The compound indicated by formula (I) or its pharmaceutically acceptable salt of the application has good inhibiting effect to PDE5 With good pharmacokinetic profile, there is suitable half-life period and biological metabolism in vivo, thus, it is easy to develop and be Clinical medicine.

Detailed description of the invention

In the following description, including certain concrete details are to provide comprehensive reason to each disclosed embodiment Solution.However, those skilled in the relevant art are not, it will be recognized that use one or more of these concrete details, and use other Embodiment can be achieved in the case where method, component, material etc..

Unless required in addition of the application, in claims in the whole instruction and thereafter, word " comprising " and " packet Containing " it should be interpreted that meaning open, including formula, i.e., " including but not limited to ".

" embodiment " mentioned in entire this specification or " embodiment " or " in another embodiment " or " in certain embodiments " mean include in an at least embodiment it is relevant to described in the embodiment with specific reference to Element, structure or feature.Therefore, throughout the specification different location occur phrase " in one embodiment " or " in reality Apply in scheme " or " in another embodiment " or " in certain embodiments " same embodiment need not be all referred to.In addition, Key element, structure or feature can combine in one or more embodiments in any suitable manner.

It should be appreciated that the article " one " for the singular used in present specification and appended claims (correspond to English " a ", " an " and " the ") includes the object of plural number, unless it is other in text it is manifestly intended that.It is also understood that Term "or" usually with it includes the meaning of "and/or" and uses, unless in text in addition it is manifestly intended that.

Definition

Term " carrier " is defined as the compound for being conducive to introducing compound into cell or tissue.For example, dimethyl sulfoxide It is typically used as carrier, this is because it is easy to for certain compounds being introduced into the cell or tissue of organism.

Term " pharmaceutically acceptable carrier " include but is not limited to by national drug food control office approve and can For any adjuvant of mankind or animal, carrier, excipient, glidant, sweetener, diluent, preservative, dyestuff/colorant, Flavor potentiator, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isoosmotic pressure agent, solvent or emulsifier etc. are to medicine Compositions various forms of carriers without side-effects.

Term " pharmaceutically acceptable salt " means the biological effect for retaining the PDE5 inhibitor of the application and property and is not Biologically or other those of unacceptable salt of aspect.For example, pharmaceutically acceptable salt does not interfere the work of the application Inhibit the beneficial effect of PDE5 with agent comprising " pharmaceutically acceptable acid-adducting salt ".

Term " pharmaceutically acceptable acid-adducting salt " refers to those of the biological effectiveness for keeping free alkali and property salt, institute It is suitable biologically or otherwise and formed using inorganic acid or organic acid to state acid-adducting salt, it is described inorganic Acid is such as, but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc., the organic acids such as, but not limited to, acetic acid, 2,2- bis- Monoxone, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzene sulfonic acid, benzene carboxylic acid, 4- acetamido benzene carboxylic acid, camphoric acid, Camphor -10- sulfonic acid, capric acid, caproic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexyl sulfamic acid, dodecyl sulphate, Ethane -1,2- disulfonic acid, ethane sulfonic acid, 2- hydroxyethanesulfonic acid, formic acid, fumaric acid, glactaric acid, gentianic acid, glucoheptonic acid, glucose Acid, glucuronic acid, glutamic acid, glutaric acid, 2- oxo-glutaric acid, phosphoglycerol, glycolic, hippuric acid, isobutyric acid, lactic acid, cream Uronic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, Loprazolam, mucic acid, naphthalene -1,5- disulfonic acid, naphthalene -2- sulphur Acid, 1- hydroxy-2-naphthoic acid, niacin, oleic acid, orotic acid, oxalic acid, palmitinic acid, pamoic acid, propionic acid, pyroglutamic acid, acetone Acid, salicylic acid, 4-ASA, decanedioic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-methyl benzenesulfonic acid, trifluoro second Acid, undecenoic acid etc..

Term " mammal " includes people and domestic animal, such as laboratory animal and house pet, as cat, dog, pig, ox, sheep, Goat, horse and rabbit and non-performing animal, such as wild animal.

Term " pharmaceutical composition " refer to the application compound with usually by this field received by bioactive compound The medium for being delivered to the mammals such as the mankind is formed by preparation.Such medium includes all pharmaceutically acceptable loads Body, diluent or excipient.Pharmaceutical composition is conducive to administration of the compound to organism.There are a variety of methods in the art Compound or pharmaceutical composition are administered, including but not limited to oral administration, drug administration by injection, inhalation, parenteral are given Medicine and local administration.

Term " pharmaceutically acceptable " is defined as not eliminating carrier, the excipient or dilute of the bioactivity of compound and property Release agent.

Term " therapeutically effective amount " refers to when to mammal, when preferably the mankind being administered, the compound of the application is enough to have Effect treats mammal, the preferably disease relevant to PDE5 of the mankind or the amount of morbid state.According to compound, morbid state And its age of seriousness and mammal to be treated, the amount for constituting the application compound of " therapeutically effective amount " will Difference, but those skilled in the art can according to usage determine the application compound according to the knowledge and the disclosure of its own Amount.

The mammal with related disease or illness, the preferably mankind are covered in " treatment " used herein or " treatment " In treatment-related disease or morbid state, and include:

(I) prevent disease or morbid state occurs in mammals, especially when the mammal is susceptible in the disease Diseased state, but when being not yet diagnosed with this morbid state；

(II) inhibit disease or morbid state, that is, prevent its generation；Or

(III) alleviate disease or morbid state, even if disease or morbid state subside.

Specific embodiment

On the one hand, this application involves the compound indicated by formula (I) or its pharmaceutically acceptable salt:

It is potent selective PDE5 inhibitor by the compound that formula (I) is indicated, with good pharmacokinetic Property is learned, and there is suitable half-life period and biological metabolism in vivo, can satisfy the needs of patient.

Pharmaceutical composition

On the other hand, this application involves pharmaceutical composition, it includes pharmaceutically acceptable carrier, excipient or diluent with And the compound or its pharmaceutically acceptable salt of therapeutically effective amount indicated by formula (I):

In certain embodiments, pharmaceutical composition is tailored to oral administration, buccal administration, intravenous injection, abdomen The pharmaceutical dosage form of intracavitary administration, subcutaneous injection, intramuscular injection, sucking or Epidermal administration etc. is preferably administered orally or sucks and gives Medicine.

In certain embodiments, pharmaceutical composition is made into suitable dosage form, including but not limited to tablet, capsule, Pastille, pill, granule, powder agent, solution, emulsion, suspension, dispersion, syrup, gelling agent or aerosol agent.

In certain embodiments, pharmaceutical composition also contains pharmaceutically acceptable surfactant, film forming matter, coating Auxiliary agent, stabilizer, dyestuff, corrigent, aromatic, fragrance, excipient, lubricant, disintegrating agent, glidant, solubilizer, filling Agent, solvent, diluent, suspending agent, osmotic pressure regulator, buffer, preservative, antioxidant, sweetener, colorant and/or Adhesive.Pharmaceutically acceptable carrier, excipient or diluent for therapeutical uses are well known in field of medicaments, and Such as in Remington ' s Pharmaceutical Sciences (Remington pharmaceutics), 18th Ed., Mack By describing in Publishing Co., Easton, PA (1990), entire contents are incorporated herein by reference herein.

The pharmaceutical composition of the application can produce according to known methods, for example, passing through conventional mixing, dissolution, grain The conventional practices such as change, manufacture pastille, grinding, emulsification, packing, retention or tabletting are produced.

Therefore, according to the application, used pharmaceutical composition can be used one or more pharmaceutically acceptable excipient, Carrier, diluent and/or auxiliary material carry out being configured to the available preparation of pharmacy in conventional manner.Suitable preparation depends on selected Administration route.Any suitable preparation technique, carrier and excipient in this field can be used.

Therapeutical uses

Another aspect, this application involves the compound indicated by formula (I) or its pharmaceutically acceptable salt in preparation for controlling The purposes in the disease relevant to PDE5 of mammal or the drug of morbid state is treated and/or prevents, wherein inhibiting PDE5 quilt It is considered beneficial,

In certain embodiments, the mammal is behaved.

In certain embodiments, the disease relevant to PDE5 or morbid state are erectile dysfunction.

Preparation, administration route and effective dose

The another aspect of the application be related to comprising by the preparation of formula (I) compound indicated or its pharmaceutically acceptable salt, Administration route and effective dose.Such preparation can be used for treating disease relevant to PDE5 as described above or disease shape State.

The compound of the application indicated by formula (I) or its pharmaceutically acceptable salt can be given in the form of a pharmaceutical preparation Give, including be suitable for oral administration (including buccal administration and sublingual administration), local administration or parenteral administration (including intramuscular are given Medicine, intradermal administration, Intraperitoneal medication, subcutaneous administration and intravenous administration) those of pharmaceutical preparation or the compound can be with It is administered by way of being suitable for through aerosolization, sucking or be blown into administration.General information about drug delivery system is found in Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippencott Williams&Wilkins, Baltimore Md. (1999)) in.

In many aspects, pharmaceutical preparation include: carrier and excipient (including but not limited to, buffer, carbohydrate, Antioxidant, bacteriostatic agent, chelating agent, suspending agent, thickener and/or preservative)；Water；Oil；Normal saline solution；Flavoring agent； Colorant；Antitack agent；And other acceptable additive, adjuvant or adhesives；Other drugs needed for close to physiological condition can The auxiliary substance of receiving, pH buffer, tension regulator, emulsifier, wetting agent, preservative etc..It can although should be understood that The composition of the application is given using any suitable carrier well known by persons skilled in the art, but view is administered the type of carrier Approach and become.

As is generally known in the art, the concentration of drug can be adjusted, and the pH value of solution is buffered and isotonicity It is adjusted, thus compatible with being injected intravenously.

The compound of the application indicated by formula (I) or its pharmaceutically acceptable salt well known in the art can be suitble to matchmaker Sterile solution or suspension are configured in Jie's object.Pharmaceutical composition can be sterilized by common known sterilization technology, or can be through nothing Bacterium filtering.Obtained aqueous solution can be packaged to use as former state or freeze-dried, the preparation of freeze-drying before administration with sterile solution into Row combination.

It, can be easily by acceptable by the compound of the application indicated by formula (I) or its drug for oral administration Salt combined with pharmaceutically acceptable carrier well known in the art to prepare.Such carrier can make the compound of the application It is configured to tablet, pill, dragee, capsule, lozenge, liquid agent, gelling agent, syrup, powder, suspension, elixir etc., For patient's orally ingestible to be treated.

Suitable for the pharmaceutical composition of the application include wherein active constituent with effective quantity (that is, can individual it is effectively real Now treat and/or prevent benefit amount) existing for composition.Treated one should be depended on to the effective actual amount of specific application Situation, preparation and the administration route and other factors known to those skilled in the art of kind or a variety of patient's condition, individual.According to This disclosure, a effective amount of determination of PDE5 inhibitor can be used in the limit of power of those skilled in the art Routine optimization techniques determine.

It can be determined according to animal model for the effective quantity in the mankind.For example, it can be formulated as the dosage of the mankind It realizes in animal it has been found that for effective circulation, liver, surface and/or gastrointestinal concentrations.Those skilled in the art can determine confession The effective quantity that the mankind use, in particular according to animal model experiment data as described herein.Based on animal data and other types Similar data, those skilled in the art can determine the application composition be suitable for the mankind effective quantity.

Effective quantity generally means in the PDE5 inhibitor for being related to the application by the various management in medicine or pharmaceutical technology Or any of advisory organization (such as FDA, SDA) or recommended by manufacturer or supplier or the dosage range of approval, administration Approach, preparation etc..

In addition, the suitable dosage of PDE5 inhibitor can be determined based on Vitro Experimental Results.For example, agent inhibits The external efficiency of PDE5 provides the information that can be used for developing the effective internal dosage for realizing similar biological action.

A variety of aspects have been generally described, these aspects can be more easily to understand by reference to following embodiment, unless Illustrate, otherwise embodiment is to provide and be not intended to by way of illustration to be limited.

Embodiment

The preparation (number: DDCI01) for the compound that 1 formula of embodiment (I) indicates

Step 1:

Table A

Reaction reagent and solvent shown in Table A are added into the 500mL reaction flask equipped with reflux condenser.In N₂Gas In atmosphere, the back flow reaction 6h at 120 DEG C.Fully reacting is monitored through thin-layered chromatography (TLC).After reaction solution is cooled to room temperature, It is filtered to remove Cs₂CO₃Solid uses CH₂Cl₂Wash filter cake.Concentrate the filtrate under reduced pressure it is dry, by gained residue CH₂Cl₂ Dissolution then respectively washed once with water and saturation NaCl solution respectively.The anhydrous MgSO of organic phase₄It dries, filters, is concentrated under reduced pressure To doing, crude product is obtained.Gained crude product is purified through silica gel column chromatography, obtains 24.4g pure products, yield 80%.

Step 2:

Table B

Reaction reagent and solvent shown in table B are added into the 500mL reaction flask equipped with reflux condenser.100 After reflux is stirred to react 6h at DEG C, fully reacting is monitored through TLC.Reaction solution is cooled to room temperature, is then cooled to 0 DEG C and in 0 It is stood overnight at DEG C.There is solid to be settled out, filter, filter cake first uses a small amount of CH₃NO₂Washing, then use CH₂Cl₂Wash into white.Through After drying, product 60g (white powder), yield 96% are obtained.

Step 3:

Table C

Product, the Et for deriving from step 2 are added into 1L reaction flask₃N、CH₂Cl₂Afterwards, clarified solution is stirred at room temperature into, then Ice bath is cooled to 0 DEG C, and the CH of chloracetyl chloride is slowly added dropwise₂Cl₂Solution, while keeping reaction temperature at 0 DEG C -5 DEG C.It is added dropwise Afterwards, continue (0 DEG C -5 DEG C) reactions under ice bath, and until the reaction is complete through TLC monitoring.Reaction solution is filtered, filter cake is on a small quantity CH₂Cl₂Washing, it is dry, white solid 32.4g is obtained (containing Et₃N.HCl, but be used directly in reaction in next step).It will Filtrate uses 10%K₂CO₃Solution washed once, then washed once with saturation NaCl solution, layering, the anhydrous MgSO of organic phase₄It is dry Dry, filtering is concentrated to dryness.Residue uses CH again₃OH∶H₂O=4: 1 recrystallization, obtains yellow-brown solid 31g.

Step 4:

Table D

At room temperature, product, the Et for deriving from step 3 are added into 1L reaction flask₃It after N and DMF, stirs evenly, then slowly The DMF solution of hydrazine hydrate is added dropwise, and is at room temperature stirred overnight reaction.After TLC monitors fully reacting, to anti-under ice-water bath The pure water for being slowly added to about 3 times of volumes in mixture is answered, and after being vigorously stirred 2h, stood, filtering.Filter cake is washed with water, then It is washed with isopropanol, it is dry, obtain crude product.Finally by crude product with a small amount of CHCl₃Flow back 20min, filters, dry, obtains Pure product 35.5g.

The gross production rate of step 3 and step 4 liang step is 82%.

¹HNMR (d-DMSO, 400M): 11.01 (s, 1H), 7.55 (d, J=7.6Hz, 1H), 7.29 (d, J=8.0Hz, 1H), 7.07 (t, J=7.2Hz, 1H), 7.02 (t, J=7.2Hz, 1H), 6.87 (d, J=1.2Hz, 1H), 6.80 (dd, J= 8.4,1.6Hz, 1H), 6.77 (d, J=8.0Hz, 1H), 6.09 (s, 1H), 5.12 (s, 2H), 4.44 (dd, J=11.6, 3.6Hz, 1H), 4.26 (dd, J=16.8,1.6Hz, 1H), 3.96 (d, J=17.2Hz, 1H), 3.56 (dd, J=16.0, 4.4Hz, 1H), 2.98 (dd, J=15.6,12.0Hz, 1H)¹³CNMR (d-DMSO, 100M): 166.76,165.09, 147.53,146.54,137.56,136.7,134.50,126.23,121.73,119.77,119.35,118.59,111.79, 108.43,107.40,105.27,56.05,55.89,53.81,23.94.

Embodiment 2: the inhibition to PED5

Method: being positive control calibration with Sildenafil (S1431, selleck), with homogeneous time resonance energy transfer (Homogenous Time Resolve Fluoresce, HTF) method (Cat.No. 62GM2PEB, Cisbio), according to sample pair The dose-effect relationship of PDE5A (E904, SIGMA-ALDRICH) rejection ability measures sample half-inhibitory concentration IC₅₀。

Sample	IC₅₀Value
		Cialis	111.6nM

DDCI01	33.6nM
		DDCI02^Note	566.2nM

Note: the structure of compound DDCI02 is as follows:

Embodiment 3: Pharmacokinetics research

Experimental method:

Stock solution is prepared: weighing 1.13 milligrams of Cialis, 1.15 milligrams of DDCI02 and 1.23 milligram of DDCI01, and respectively Dissolve them in the stock solution for being made that concentration is 1.00 mg/mls in 1.13,1.15,1.23 milliliters of dimethyl sulfoxide.

Sample preparation methods: a step precipitation of protein

Precipitating reagent: acetonitrile (Verapamil containing 5.00 nanograms/milliliters)

Standard curve and quality-control sample preparation: the standard curve of 5.00 microlitres of transfer or Quality Control working solution and 45.0 microlitres The centrifuge tube of blank plasma to one 1.5 milliliters.The final concentration of standard curve sample is respectively 1.00,2.50,5.00,10.0, 50.0,100,500 and 1000 nanograms/milliliter.The concentration of quality-control sample is respectively 2.50,5.00,50.0 and 800 nanograms/milliliters. Dilution quality-control sample concentration is 5000 nanograms/milliliters.

Plasma sample preparation: sample to be tested, the standard curve sample of 100 microlitres of precipitating reagent to 10.0 microlitres are shifted respectively And quality-control sample.After vortex concussion in 3.00 minutes and centrifugation (12000 revs/min) in 5.00 minutes, draw on 10 microlitres Clear liquid is analyzed for LC-MS/MS.

Number of rats: every group of 3 rats,

Administration mode: oral administration,

Blood sampling time point: 0 minute, 15 minutes, 30 minutes, 1h, 2h, 4h, 6h, 8h, for 24 hours

Experimental result:

DDCI01:

DDCI02

Cialis

Pharmacokinetics the result shows that DDCI01 in C_maxIt is substantially better than Cialis and DDCI02 in terms of AUC, and And in SD rat Half-life in vivo (t_1/2) research shows that DDCI01 ratio cialis is slightly shorter, than DDCI02 long.

Embodiment 4: normal rat erection function pharmacodynamic study

Rat blood pressure and intracavernous pressure variation detection:

Rat separates right carotid artery, passes through PE-50 silica gel catheter after 2% anaesthetized with pentobarbital (3 mg/kg) It is connected with a pressure sensor of Powerlab recorder, record arterial pressure persistently changes (rat serum when electro photoluminescence starts Beginning decline rapidly is pressed off, stimulation terminates blood pressure and restores normal quickly).Median abdominal incision is removed later, is extended to scrotum and is indulged diaphragm, cruelly Reveal two sides crus penis, crus penis is inserted into No. 23 cannula needles in left side, passes through PE-50 silica gel catheter and Powerlab recorder Pressure sensor is connected, and contains heparin-saline (250 units per ml) in conduit, basin on the left of double sided electrode stimulation test group Neuromere cavernosal nerve issues section, and adjustment Powerlab system makes the wide 2.56ms of parameter wave of electro photoluminescence pelvic ganglia, frequency Rate 7.98HZ, electric current 3mA, duration 40s, record intracavernous pressure variation.

Erection function detection: the administration of rat single oral 2 after administration, is detected for 6,24 hours by electrode stimulating nervi erigentes Animal erection function, record stimulation front and back arterial pressure changing value, intracavernous pressure changing value/blood pressure value, stimulation front and back Intracavernous pressure changing value, rat penis regression time after stimulation.Erection function primary evaluation index is intracavernous pressure variation Value, corpora cavernosa penis regression time.

Table 1: 2 hours blood pressure data (means standard deviation) after each experimental group rat administration

Note: * P < 0.05 compared with the control group, * * P < 0.01.

Blood pressure is two hours after administration detected value before # animal stimulates

Table 2: 2 hours intracavernous pressure delta datas (means standard deviation) after each experimental group rat administration

Note: * P < 0.05 compared with the control group, * * P < 0.01.

Table 3: 2 hours penis regression time data (means standard deviation) after each experimental group rat administration

Group	Stimulation front and back blood pressure difference/intracavernous pressure difference	Regression time (S)
			Negative control group	38.14±13.17	9.75±4.92
Tadalafil group	89.75±33.30	40.50±21.14*
			DDCI-01 low dose group	105.52±41.17*	38.00±10.42*
DDCI-01 middle dose group	128.64±35.20*	40.75±4.79*
			DDCI-01 high dose group	136.85±41.98**	101.00±21.56**

Note: * P < 0.05 compared with the control group, * * P < 0.01.

Table 4: 6 hours blood pressure data (means standard deviation) after each experimental group rat administration

Note: compared with the control group, difference that there are no significant

Table 5: 6 hours intracavernous pressure delta datas (means standard deviation) after each experimental group rat administration

Note: * P < 0.05 compared with the control group, * * P < 0.01.

Table 6: 6 hours penis regression time data (means standard deviation) after each experimental group rat administration

Group	Stimulation front and back blood pressure difference/intracavernous pressure difference	Regression time (S)
			Negative control group	39.30±15.86	9.50±2.52
Tadalafil group	117.16±42.07*	44.25±13.35**
			DDCI-01 low dose group	94.70±33.16*	47.75±11.79*
DDCI-01 middle dose group	106.19±16.03*	48.00±23.85*
			DDCI-01 high dose group	159.65±33.86**	64.00±19.37**

Note: * P < 0.05 compared with the control group, * * P < 0.01.

Table 7: 24 hours blood pressure data (means standard deviation) after each experimental group rat administration

Note: compared with the control group, difference that there are no significant

Table 8: 24 hours intracavernous pressure delta datas (means standard deviation) after each experimental group rat administration

Note: * * P < 0.01 compared with the control group.

Table 9: 24 hours penis regression time data (means standard deviation) after each experimental group rat administration

Group	Stimulation front and back blood pressure difference/intracavernous pressure difference	Regression time (S)
			Negative control group	49.67±5.59	8.75±1.71
Tadalafil group	107.99±32.42	41.25±10.34*
			DDCI-01 low dose group	92.05±31.72	23.75±12.84
DDCI-01 middle dose group	106.03±44.12	41.25±14.50*
			DDCI-01 high dose group	113.00±38.23	60.75±24.14**

Note: * P < 0.05 compared with the control group, * * P < 0.01.

The result shows that, after giving normal rat compound DDCI-01, basic, normal, high dosage can be significant shown in table It is poor to increase intracavernous pressure, extends penis regression time, is i.e. normal rat erection function can be remarkably reinforced in the compound.Experiment Middle tadalafil group dosage is low with DDCI-01, middle dose group evaluation result is close close to human normal dosage.

5 DDCI-01 biologically effective Journal of Sex Research of embodiment

The preparation and addition of compound: DMSO gradient dilution compound is used；Since 10mM mother liquor, diluted with DMSO three times Compound Cialis and DDCI-01.99 μ l reaction buffering is added in the every hole of diluted chemical compound plate (V96 MicroWell Plates) Liquid, then it is separately added into the compound DMSO dilution of 1 μ l, it mixes well.The every hole reaction plate (96-well microplate) adds Enter the good compound of the 5 above-mentioned dilutions of μ l；Compound it is final concentration of: 10000,3333,1111,370.4,123.5,41.2, 13.7,4.6,1.5,0.51,0.17 [nM]；

Using related kit evaluation compound to a variety of phosphodiesterases (PDE) active inhibiting effect.Specific screening The results are shown in Table 1.

Inhibiting effect of 10 compound of table to a variety of phosphodiesterase activities.

The results show that DDCI-01 shows the measurement result of other 7 PDE hypotypes, DDCI-01 is to PDE6C (IC50 > 10 μM) and (IC50=2.6 μM) of PDE11A have faint inhibiting effect, to PDElA, 2A, 3A, 4A1A and 7A then without obviously Inhibiting effect (at 10 μM, it is 0% to the inhibiting rate of enzymatic activity).

Claims

1. compound or its pharmaceutically acceptable salt that formula (I) indicates,

2. pharmaceutical composition, it includes the compound indicated by formula (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable loads Body or excipient,

3. pharmaceutical composition, it includes the compound indicated by formula (I) or its pharmaceutically acceptable salt and pharmaceutically acceptable dilute Agent is released,

4. described in the compound described in claim 1 indicated as formula (I) or its pharmaceutically acceptable salt or Claims 2 or 3 Pharmaceutical composition preparing disease relevant to 5 type phosphodiesterases or disease for treating and/or preventing mammal Purposes in the drug of state, wherein inhibit 5 type phosphodiesterases be considered as it is beneficial,

5. purposes as claimed in claim 4, wherein the mammal is behaved.

6. purposes as claimed in claim 4, wherein the disease relevant to 5 type phosphodiesterases or morbid state are to erect Dysfunction.

7. the purposes as described in any one of claim 4-6, wherein the drug is for being administered orally, local administration, intramuscular Administration, intradermal administration, Intraperitoneal medication, subcutaneous administration, intravenous administration or inhalation.

8. the purposes as described in any one of claim 4-6, wherein the drug is for being administered orally.

9. the purposes as described in any one of claim 4-6, wherein the drug be selected from tablet, capsule, pastille, pill, Granule, powder agent, solution, emulsion, suspension, dispersion, syrup, gelling agent or aerosol agent.

10. purposes as claimed in claim 9, wherein the pill is dragee.

11. purposes as claimed in claim 7, wherein the drug is selected from tablet, capsule, pastille, pill, granule, powder Last agent, solution, emulsion, suspension, dispersion, syrup, gelling agent or aerosol agent.

12. purposes as claimed in claim 11, wherein the pill is dragee.

13. purposes as claimed in claim 8, wherein the drug is selected from tablet, capsule, pastille, pill, granule, powder Last agent, solution, emulsion, suspension, dispersion, syrup or gelling agent.

14. purposes as claimed in claim 13, wherein the pill is dragee.